The field of schizophrenia research needs innovative research programs that utilize basic neuroscience approaches and translate their findings into clinically meaningful goals. The goal of this proposal is to develop a pharmacologist with a background in industrial chemistry into an independent investigator of the neurobiology of schizophrenia. The broad-based training environment at UNC, including exposure to a talented multidisciplinary faculty and interaction with a critical mass of research fellows of diverse backgrounds is ideal for such translational endeavors and career development. The candidate will develop comprehensive knowledge of developmental neurobiology, assimilate current schizophrenia literature and acquire necessary research skills through didactic training, tutorials and original research. The research project proposes to investigate generally the role of neurosteroid influences on brain development and specifically if their response to stress could alter prefronal cortical neurodevelopment in a permanent manner that affects brain function and behavior in the adult. It is widely believed that schizophrenia is an environmentally modulated, genetically mediated neurodevelopmental disorder. Non-specific stress is the developmental factor most closely associated with increased schizophrenia vulnerability. Neurosteroids, including 3alpha-hydroxy-5alpha-pregnane-20-one (allopregnanolone or 3alpha,5 alpha-THP) and 3alpha,21- dihydroxy-5alpha-pregnane-20-one (THDOC) are rapidly induced after stress stimulus in adults and neonates. Furthermore, allopregnanolone and THDOC are potent modulators of GABAA receptors and likely to regulate cortical development. Finally, aberrant cortical development is thought to underlie altered indices of GABAergic neurotransmission present in post-mortem brain tissue of schizophrenics. To test the hypothesis that GABAergic neurosteroid levels play a role in normal cortical development, neurosteroid levels will be altered during the first week of rodent life and cortical morphology, cytoarchitecture and sensory gating measured 80 days later. Preliminary data suggest that neonatal administration of allopreganolone produces long-lasting changes in prefrontal cortex interneuron cell localization and prepulse inhibition that resemble the loss of neural matter and sensory-gating deficits evident in schizophrenics. These studies could represent a model of the role of neurosteroid on stress in brain development.